Autism Spectrum Disorder, Klinefelter Syndrome, and Chromosome 3p21.31 Duplication: A Case Report

Scott W. Stuart, MD, MS; Casey H. King, BA; G. Shashidar Pai, MD

In This Article


Children with ASD often have a wide array of physical features and cognitive abilities. Family studies have demonstrated recurrence as high as 50% in an identical twin of an affected proband.[4] Heritability estimates as high as 90% have been reported.[4] Many studies have shown identifiable discrete genetic disorders and other susceptibility loci associated with ASD.[3,4,5,6,7,8,9,10] However, the immense diversity in the clinical presentation has stymied the progress in identifying consistent genetic markers that correlate with core ASD behaviors. Identified chromosomal abnormalities account for 2% to 5% of ASD cases and generally involve an unbalanced translocation, inversion, ring, deletion, or duplication of various chromosomes.[4,9] Specific chromosomal abnormalities include, but are not limited to, a deletion (as seen in Prader-Willi and Angelman syndromes) or duplication within 15q11-q13, deletions within 18q, Xp22.3, 2q37, 22q13, and such sex chromosome aneuploidies as 47,XXY, 47,XYY, and 45, X/46, XY mosaicism.[3,4,5,6,7,8,9,11] Several single-gene disorders associated with ASD have been identified, including fragile X syndrome (FMR1), neurofibromatosis (NF1), Rett syndrome (MECP2), and tuberous sclerosis (TSC1 and TSC2) as well as NLGN4 and PTEN gene sequence variants.[3,4,5,6,7,8,10,12,13] Metabolic disorders, such as untreated phenylketonuria, homocystinemia, and certain organic acidemias in addition to in utero exposure to alcohol, valproic acid, and the rubella virus, have also been associated with ASD.[3,9,12,14] However, most cases of ASD are idiopathic. Genetic or metabolic disorders are identified in only 10% to 15% of all ASD patients assessed.[3,4,5,6,7,8,15,16,17]

KS has been well characterized in the medical literature, and several case reports have been published describing the relationship between KS and ASD.[3-8] However, this patient also had a concurrent 3p21.31 duplication identified by the probes RP11-68104 and RP11-578F5 in the SignatureChip Version 4.0. Review of PubMed ( and the European Cytogenetics Association Register of Unbalanced Chromosome Aberrations ( did not identify additional cases to provide further insight to the significance of this finding. Reported cases of "duplication 3p syndrome" show phenotypic features, including microcephaly, square face, temporal indentation, frontal bossing, hypertelorism, down-turned corners of the mouth, micrognathia, and short neck.[19,20] Other than microcephaly, none of these findings was present in our patient.

Because the mother had an apparently similar duplication, a clinician may consider this finding as an insignificant genetic polymorphism. Statistically, approximately 2 of 3 findings on CGH microarray studies are deemed inconsequential polymorphisms primarily because they occur in clinically normal relatives.[9,21] In our patient, when it was discovered that the mother also had this finding, the relevance of the 3p21.31 duplication was reexamined. While a formal diagnostic work-up could not be completed, the patient's mother had many characteristics of bipolar disorder but no reported behaviors that suggested ASD. A potential linkage between 3p21 and bipolar disorder has been reported, although the significance in this particular case is inconclusive.[22] An identical 3p21.31 duplication was found in only 1 patient out of 15,000 samples assessed by Signature Genomics (personal communication, July 17, 2007). That child had developmental delay, and further investigation determined that the father also had the duplication. The relevance of the 3p21.31 duplication with regard to behaviors associated with ASD is unclear at this point.

Historically, a child with a developmental delay did not necessarily have genetic evaluation unless there was a suspicion of a recognizable genetic syndrome by history or examination. It was not until June of 2006 that the first guidelines were published to provide guidance for genetic evaluation of a child with developmental delay in recognition that many genetic disorders associated with subtle genomic changes do not have a discrete clinical phenotype.[23] Evidence-based medicine for best practices has yet to be established specifically for genetic evaluation of ASD. As a result, the approach to a genetic evaluation of a child with an ASD has varied substantially.[3,4,6,8,9,10,13,16,17] Evaluation may include, but is not limited to, high-resolution chromosomes; fluorescent in-situ hybridization (FISH) for 15q11 duplications; FMR1 and MECP2; PTEN gene sequencing; CGH microarray; testing of urine organic acids, serum amino acids, plasma homocysteine, and lead levels; conducting a sterol profile; and electroencephalography and magnetic resonance imaging of the head. High-resolution chromosome analysis has revealed a chromosomal anomaly in up to 5% of ASD cases.[4,9] The yield from subtelomeric FISH and metabolic assessment is very low (<1%).[3,4,8] Isolated FISH probe gene mutation analysis for specific syndromes, such as Angelman or fragile X, may be discovered in 5% to 7% of ASD patients.[3,6,8,9,11,12,15,21]

CGH microarray allows investigation of the human genome at a resolution of 5 to 10 times that of high-resolution chromosome analysis.[9] This improved sensitivity has led to the discovery of clinically relevant genetic abnormalities in children with mental retardation and congenital anomalies that were missed by high-resolution chromosomal assessment.[9] Jacquemont and colleagues conducted CGH microarray analysis at 1-MB resolution on 29 patients with idiopathic ASD. Thirty-three chromosome gains or losses were detected in 22 patients. Of these 23 variants, 69% had been previously described as normal variants [9] and the remaining 10 were considered clinically relevant and submitted to global genetic databases.[9]

Such observations emphasize the importance of clarifying the origin of a genetic variation by studying the parents for comparison. The finding of an identical genetic variant in a healthy parent suggests a clinically insignificant polymorphism. However, if the parent has a concerning trait -- as in our case -- the likelihood of a clinically significant finding increases substantially. The CGH microarray technology substantially increases the frequency of abnormal results and in turn provides new challenges to clinicians in determining their clinical significance.[21] Careful clinical documentation is critical in improving our understanding of these rare yet important occurrences.


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